1. Field of the Invention
This invention relates to intermediate compounds useful for the synthesis of 16-phenoxy-prostatrienoic acid derivatives and a preparing method thereof. Because 16-phenoxy-9-keto-prostatrienoic acid derivatives (enprostil) possess antisecretory activity, they are useful in treating gastrointestinal disorders. 16-Phenoxy-9.alpha.-hydroxyprostatrienoic acid derivatives (fenprostalene) are useful as luteolytic agents in female mammals, since they possess luteolytic activity.
2. Description of the Conventional Art
Muchowski et al., U.S. Pat. No. 3,985,791, describe the invention of 16-phenoxy and 16-(o, m, or p)-substituted phenoxy derivatives of 9.alpha.,11.alpha.,15.alpha.-trihydroxy-17,18,19, 20-tetranorprosta-4,5,13-trans-trienoic acids and multistep process for the production of these compounds. Their approach to the fenprostalene (formula II, Z=.alpha.-hydroxyl) involves an intermediate compound of the general formula I, wherein R.sup.1 and R.sup.2 are acetyl and P is methoxycarbonylethyl by using somewhat expensive 4-pentynoic acid and an excessive amount of explosive diazomethane. They introduced an allenyl group in fenprostalene from this intermediate by the reaction with lithium dimethycuprate. The specific formation of protonated allene from propargylic ester is sensitive to various factors depending on the kind of propargylic derivatives, cuprate reagents, reaction temperature, work-up conditions, etc. (P. Crable et al., Tetrahedrom Lett., 1975, 4615; C. Sahlberg et al, Acta. Chem. Scand., 1982, B 36, 179). In addition, the process of U.S. Pat. No. 3,985,791 requires accurate control in order to avoid the formation of undesirable alkylated allene isomers and alkylated acetylene isomers which may be formed by the introduction of protonated allenes (P. Crable et al., Tetrahedron, 1979, 35, 2931; A. Claesson et al., Tetrahedron Lett., 1975, 1509; A. Alexakis et al., J. Am Chem. Soc., 1990, 112, 8042; T. L. MacDonald et al., J. Org. Chem., 1980, 45, 4740).
Van Horn et al. (U.S. Pat. No. 4,178,457) disclose enprostil and a process for manufacturing thereof. Van Hom's process is a three step process consisting of protecting 11.alpha. and 15 hydroxyl groups of the compounds of U.S. Pat. No. 3,985,791, selective oxidation of 9-hydroxyl group to 9-keto group and removal of protecting groups.
Cooper et al. (U.S. Pat. No. 4,600,785) describes a multistep process for the synthesis of enprostil using an intermediate compound in formula I, wherein R.sup.1 is t-butyldimethylsilyl, R.sup.2 is hydrogen, and P is hydrogen. They prepared the intermediate compound via a 6-step sequence starting from 1.alpha.-hydroxy-4.alpha.-(tetrahydropyran-2-yloxy)-3.beta.-(3.alpha.-(tet rahydropyran-2-yloxy)-4-phenoxy-1(E)-buten-1-yl)-cyclopent-2.alpha.-yl)acet icacid lactone consisting of hydrolysis of the lactone ring, esterification of the acid to methyl ester, protection of the 9-hydroxyl group, reduction of methyl ester, oxidation of the resulting alcohol to aldehyde, and addition of an ethynyl group. They introduced an allenyl group in enprostil from this intermediate I by Claisen rearrangement and one-carbon elongation via a multistep process. Their approach requires a lengthy reaction due to the need to selectively functionalize the C-6 and C-9 hydroxyl groups (PG numbering) and one-carbon elongation.